Key Ideas

Targeted therapy is moving earlier into lung cancer treatment. A RET inhibitor now shows a dramatic reduction in recurrence when given after surgery for early-stage RET fusion-positive non-small cell lung cancer, joining similar approaches already used for EGFR- and ALK-driven disease. Not every adjuvant strategy succeeds, however: a large trial of adjuvant immunotherapy in patients without a targetable mutation was negative. In small cell lung cancer, bispecific antibodies represent a new frontier for treatment.

A New Standard for Early-Stage, RET Fusion-Positive Disease

Adjuvant targeted therapy already has a track record in early-stage non-small cell lung cancer (NSCLC) driven by EGFR or ALK alterations, where it has meaningfully reduced recurrence after surgery. RET fusions, present in only about one to two percent of NSCLC cases, had not previously had a comparable option in the curative-intent setting, despite high recurrence rates after surgery or radiation alone.

The phase 3 LIBRETTO-432 trial changes that. In this global, placebo-controlled study, 151 patients with resected stage IB-IIIA RET fusion-positive NSCLC were randomized to adjuvant selpercatinib or placebo for up to three years. In the primary analysis population (stage II-IIIA), selpercatinib reduced the risk of recurrence, a new primary lung cancer, or death by 83 percent compared with placebo (hazard ratio, 0.17), with two-year event-free survival of 91.5 percent versus 61.1 percent. When patients with stage IB disease were included, the risk reduction remained a striking 84 percent. Overall survival data remain immature, but the trend favors selpercatinib. This is the first randomized phase 3 trial of a RET inhibitor in the adjuvant setting, and it reinforces a broader point: comprehensive biomarker testing belongs at diagnosis, not just once disease has become metastatic, since it can change management even in early-stage disease.

Not Every Adjuvant Strategy Works

It's worth balancing that success against a recent negative result. The ECOG-ACRIN EA5142 (ANVIL) trial tested adjuvant nivolumab after standard surgery and chemotherapy in resected NSCLC without EGFR or ALK alterations, regardless of biomarker status otherwise. Across the full study population, nivolumab did not improve disease-free survival compared with observation (hazard ratio, 0.97), and even in patients with high PD-L1 expression (50 percent or greater), the difference was not statistically significant. This negative trial matters clinically: it argues against extending adjuvant immunotherapy broadly to biomarker-unselected patients outside of the perioperative regimens (such as neoadjuvant chemo-immunotherapy) that have already shown clear benefit, and it's a useful reminder that not every plausible strategy in oncogene-negative disease pans out, even when the underlying biological rationale is sound.

Advancing Second-Line Options in Small Cell Lung Cancer

Small cell lung cancer (SCLC) has had far fewer treatment advances than NSCLC, and outcomes after progression on first-line platinum-based chemotherapy have historically been poor, with second-line chemotherapy options offering only modest benefit. Tarlatamab, a bispecific antibody engineered to bind both DLL3 (a protein expressed on the surface of most SCLC cells but minimally on healthy tissue) and CD3 on T cells, changes that calculus.

In the phase 3 DeLLphi-304 trial, 509 patients with SCLC that had progressed during or after platinum-based chemotherapy were randomized to tarlatamab or investigator's choice of chemotherapy (topotecan, lurbinectedin, or amrubicin). Tarlatamab improved median overall survival to 13.6 months compared with 8.3 months with chemotherapy, a 40 percent reduction in the risk of death, along with improved progression-free survival and better patient-reported symptom control. It was thanks to the DeLLphi-304 trial that a new category of therapies is now available for 2<sup>nd</sup> line small cell lung cancer.

Another candidate that may be added to the limited arsenal of 2<sup>nd</sup> line treatments available for small cell lung cancer is ivonescimab. Ivonescimab, like tarlatamab, is a bispecific antibody. The difference is that it targets PD-1, and VEGF. A recent single arm phase 2 study (Fan Y, et. Al 2026) found that treatment with ivonescimab in combination with liposomal irinotecan in the second line setting for small cell lung cancer led to an objective response rate of 61.7%, along with a median PFS of 9.8 months. Ivonescimab in combination with liposomal irinotecan may become another much needed option for small cell lung cancer patients in the second line setting.

For Patients

If you or a loved one has lung cancer, two points from this year's data are worth raising with your oncologist. First, if surgery is part of the treatment plan, ask whether comprehensive genomic testing of the tumor has been done or is planned. A newly available option, a RET-targeted pill taken after surgery, has been shown to sharply cut the chance of the cancer returning in patients whose tumors carry a RET alteration, joining similar targeted options already used for other genetic subtypes. This kind of testing increasingly determines what's available to you, even at an early stage.

Second, for small cell lung cancer that has progressed after initial chemotherapy, a newer immune-based treatment called tarlatamab, given as an infusion rather than a pill, has shown better survival and fewer severe side effects than standard second-line chemotherapy. If your cancer has progressed after first-line treatment, it's worth asking whether this option is appropriate for you.

Key Takeaways

  • Adjuvant selpercatinib reduced the risk of recurrence or death by 83 to 84 percent compared with placebo in early-stage RET fusion-positive NSCLC, the first randomized phase 3 result for a RET inhibitor in this setting.

  • A large trial of adjuvant nivolumab in resected NSCLC without EGFR or ALK alterations (ECOG-ACRIN EA5142/ANVIL) did not improve disease-free survival, underscoring that not all adjuvant immunotherapy strategies succeed outside of established perioperative regimens.

  • In small cell lung cancer, tarlatamab, a DLL3xCD3 bispecific antibody, improved median overall survival to 13.6 months versus 8.3 months with chemotherapy in the second-line setting. Newer agents such as ivonescimab, a PD-1 and VEGF bispecific antibody, also demonstrates promising initial results.

References

  1. Goldman JW, Wu YL, Hochmair M, et al. Event-free survival with adjuvant selpercatinib in stage IB-IIIA RET fusion-positive NSCLC: primary results of the phase 3 LIBRETTO-432 trial. Presented at the 2026 ASCO Annual Meeting; published in the New England Journal of Medicine, 2026.

  2. Chaft JE, Sun Z, Rudin CM, et al. Adjuvant nivolumab versus observation in resected non-small cell lung cancer (ECOG-ACRIN EA5142, ALCHEMIST). Presented at the 2026 ASCO Annual Meeting; published in JAMA, 2026.

  3. Mountzios G, Sun L, Cho BC, et al. Tarlatamab versus chemotherapy as second-line treatment for small cell lung cancer: primary analysis of the phase 3 DeLLphi-304 trial. Presented at the 2025 ASCO Annual Meeting; published in the New England Journal of Medicine, 2025.

  4. Yun Fan et al. Efficacy and safety of ivonescimab combined with liposomal irinotecan in patients with small-cell lung cancer (SCLC) progressing after first-line chemoimmunotherapy: A multicenter, phase 2 study.. J Clin Oncol 44, 8007-8007(2026).

  5. Eli Lilly and Company. Retevmo (selpercatinib) delivers substantial event-free survival benefit as adjuvant therapy in early-stage RET fusion-positive lung cancer. Press release, February 16, 2026.